Nu4-(mercapto-acyl)-(p-amino-benzenesulfonamides) and method of preparing same



Patented pr. 15, 1947 N (MERCAPTO-ACYL) (n -I'AM-I'N0-:BENZENE- SULFONAMIDES) AND METHOD OF PRE- PARING SAME 1 William A. Lott, Maplewood and- Kathryn, A. Losee, New Brunswick, N. J and Andrew Ellis OKeefle, United States Army, assignors to E. R.

. Squibb & Sons, New York, N Y., a corporation.

of New York No-Drawing.- Application May 17,1943, Serial-No. 488,805

This invention relates to,, and .has for its obje'ct'the provision of: [A],'N -(mercapto-acyl)- (p amino benzene sulfonamides); [B], S- (heavy-metal) derivatives; of [A]; [C1, salts; of [A]; and [B] withbases: and [D], methodsof producing [A], EBLand'ECl. These compounds are promising therapeutic-agents; the S-(heavymetal) derivatives [B] and salts: thereof [Cl being-especially promising because. of; their; combination of the chemotherapeutic;action ofthe, sulfonamides with the therapeutic action of the heavy-metals.

The term p-amino=benzene-sulfonamide" is used herein to. designate the recognized, genus composed of sulfanilamide and, its N'.-s.uhstitil tion products, such assuIiathiazole andsulfacetamide.

The invention comprises: especially compounds of the formula 1 21" 1: [wherein R represents a member of the class consisting of hydrogen andtheheavyz-metals, R, represents a member of the. class consisting of hydrogen, alkyl (preferably lower alkyl), aryl (preferably phenyl),-and aralkyl, R represents the N1 radical of a p-amino-benzenersulfonamide, and a: representsthe valence of, R1; and salts of these compounds with bases. A representative compound of this invention, the sodium salt of the S-silver derivative of N- -thioglyoolyl sulfathiazole, has the structural formula 77 Ag-S-CHz-C O-NH-O-SOa-El- S Compounds [A] may be conveniently prepared by heating a mixture of a p-amino-benzene-sulfonamideand a mercaptocarboxylic acid- (preferably athioglycolic acid, 1. e., an acid of the:

' by an open-endmanometer, isheatedunderpres- 10. Claims; ,(Cl. 260-239.6)

The following examples are illustrative of the invention:

EXAMPLE 1 Preparation of N thioylycolyl-sulfcmlamide A mixture of 17.2. g.. sulfanilamide and 27.6 g. thioglycolic acid is placed in a sealed tubeunder nitrogen and heated at 150 C. for 3 hours. The

solid, crystalline mass, obtained on cooling, the reactionwmixture, (a clear water-White liquid), is

-- washed 3 times with water and: once with alcohol,

and dried intvacuoc The product, N -thioglycolyl-sulfanilamide, obtained in. ayield of 22 gt,

A mixture of 25 g. sulfapyridine and 27.6 g. thioglycolio acid, in. asmall ,glass capsule sealed sure and under nitrogen at 150 C. for .2 hours; The reaction product is washed twice-with water, once with ethylalcohohand once with ether; and after drying forabout. 1-6. hours in vacuo, it. is Washed twice with ether 'and again. dried invacuo. The product, N -thioglycolylesulfapyridine, is obtained in a yield of 22 g.

EXAMPLE 3 Preparation of N thioglycolzll-suljathiazole On drying. over P205 for about 16 hours and then over sulfuric acid, the product, N -thioglycolylsulfathiazole, melts at 196 'C.

EXAMPLE" 4 I Preparation of an S gold derivative of; ZW- thz'o 5 g;- of N -thioglycolyhsulfathiazole is dissolved in 30.4 cc. N/l sodium hydroxidesolution and' 27 cc. bromauric acidis added. The reaction mixture is shaken (the reddish-brown precipitate formed becoming white), made acid to Congo red, and; allowed to stand; about: 16 hours; and the precipitate-formedisseparatedby centrifiugation '3 and dried in vacuo. The product, an S-gold derivative of N -thioglycolyl-sulfathiazole, is obtained as a White powder melting at 186-192 C.,

in a yield of 4.5 g.

EXAMPLE 5 amass"? Alternative preparation of an S-gold derivative of N -thioglycolyZ-suljanilamide Y EXAMPLE 6 Preparation of an S-cadmz'am derivative of N thioglycolyl-snljathiazole 5 g. N -thioglycolyl-suliathiazole is dissolved in 30.2 cc. N/ 1 sodium hydroxide solution, and 1.4 g cadmium chloride is added, the precipitate formed beingdissolved by shaking. On addition of 15.1 cc, N/1 HCl solution, a gelatinous White precipitate forms. The precipitate is removed by centrifugation, washed with water, and dried in vacuo. The product, an S-cadmium derivative of N -thioglycolyl-sulfathiazole, is'obtained as a White powder in a yield of 7.0g..

EXAMPLE .7.

Preparation of an. S-cadmium derivative of N thioglycolyl-saljanilamide 5 g. N -thioglycolyl-sulfanilamide is dissolved in 20.3 cc. N/l sodium hydroxide solution, and 1.8 g. cadmium chloride is added. The white. gelatinous precipitate formed is centrifuged ofi, washed with water, and dried with alcohol and thiazole in 90% alcohol. The white precipitate which forms is filtered ofi, washed with water and dried. The product is believed to have the formula EXAMPLE 10 Preparation of S-(trzvalent antimony) derivatives of N -:hioglycolyl-sulfathiazole (1) 100 cc. of a 0.1 molar solution of antimony trichloride is added to 100 cc. of a 0.1 molar solution of N thioglycolyl-sulfathiazole in 90% alcohol (the-precipitate formed redissolving almost immediately). Water is then added, and the immediately-formed white precipitate is filtered off 'anddried. The product is believed to have then in vacuo. The product, an S-cadmium derivative of N -thioglycolyl-sulfanilamide, is obtained as a white powder in a yield of 6.5 g.

EXAMPLE 3 Preparation thioglycolyl-suljathiazole A: solution of 3.2 g. bismuth triohloride in glacial acetic acid is added dropwise to a solution of.3.5 g. of the sodium salt of N -thioglycolylsulfathiazole in glacial acetic acid; and the pre cipitate, an S-bismuth derivativeof N -thioglycolyl-sulfathiazole, isfiltered off and dried.

EXAMPLE 9 1 Alternative preparation of S-bz'smnth derivatives of N -thioglycolyl-suljath azole ('1) 100 cc. of a 0.1 molar solution of bismuth trichloride in propylene glycol is added to 100 cc. of a 0.1 molar solution of N -thioglycolylsulfanthiazole in 90% alcohol (the precipitate which forms'redissolving almost immediately). Water is then added, and the white precipitate formed is filtered .ofi anddried. The product is believed to have the formula O=Bi--'SCHz-CO-(N4-radical of sulfathiazole) (2)" 33 cc. of a 0.1 molar solution of bismuth trlchloride inpr'opy-leneglycol is added to 100 ced of a 0.1 molar solution of N -thiog1ycolyl-sulfaof an S-bz'snzuth derivative of N the formula ,O=Sb-SCH2-C O-(N -radical of sulfathiazole) (2) 67 cc. of a 0.1 molar solution of antimony trichloride is added to 100 cc. of a 0.1 molar solution of N -thioglycolyl-sulfathiazole in 90% alcohol (a slight precipitate forming). Water isimmediately added; and the white precipitate formed is filtered off and dried. The product is; believed to have the formula (3) 33 cc. of a 0.1 molar solution of antimony trichloride is added to 100 cc. of a 0.1 molar solutionof N -thioglycolyl-sulfathiazole in 90% alcohol. The white precipitate which forms immediately is filtered off, dried, redissolved in 10% sodium hydroxide solution, and reprecipitated by addition of 10% hydrochloric acid solution; and the precipitate is filtered off and dried. The product is believed to have the formula SblI -'-S-CH2-CO(N -radical of sulfathlazole) la y Y EXAMPLE 11 I 7 Preparation of S-(pentavalent antimony) de- V rivatzves of N%-thioglycolyl-salfathiazole k (1) cc. of a 0.1 molar solution of antimony pentachloride is added to 100 cc. of a 0.1 molar.

solution of N -thioglycolyl-sulfathiazole in 00%; alcohol. Water is then added, and the white 4 precipitate which forms immediately is filtered off and dried. The product is believed to have theformula (2) 20 cc. of a 0.1 molar solution of antimony; pentachloride is added to 100 cc. of a 0.1 molar solution of N -thioglycolyl sulfathiazole in alcohol. The white precipitate which forms im -i al of sulfathimediately is filtered off and dried. The product is believed to have the formula I azo le) ]5 EXAMPLE 12 Preparation of the S-silver derivative of N -thio-f gZycolyZ-suliathiaeole 100. cc.'of. a 0.1 normal solution of. silver nitrate: is added to cc. of a 0.1; molansoiutiomof;

N -thioglycolyl-sulfathiazole in 90% alcohol.

S The S-silver derivative of N -thloglycolyl-sulfathiazole forms as a yellow precipitate, which is filtered ofi, dried, and purified by redissolving in 10% sodium hydroxide solution and reprecipitating by addition of 10% hydrochloric acid solution.

EXAMPLE 13 Preparation of the sodium salt .of the S-silver derivative of N -thioglycolyl-sulfathiazole 4.35 g. of the s-silver derivative of N -thiogylcolyl-sulfathiazole described in Example 12 is dissolved in an equimolecular quantity of normal sodium hydroxide solution (10 00.), the resulting o ution havin pH f l0.. 0n v p i he s luti to dryness under a hi h vacuum, th salt is obtained as a yellowpowder which is completely water-soluble. The product is then thorou y dried. The sil er s no p e t te by addition of sodium hydroxide, sodium chloride, or potassium iodide, but is precipitated by addition of ammonium sulfide.

EXAMPLE 1i Preparation of the sodium salt (i. e., N'-s0diumderivative) of N -thiog ly'colyZ-sulfathiazole Preparation of the sodium salt of an S-gold derivative of N -thioglycolyl-sulfathiazole An aqueous solution of the salt is obtained direct by adding the S-gold derivative of N thioglycolyl-suliathiazole described in Example 4 to a molecular equivalent of sodium hydroxide in aqueous solution; and the salt itself is obtained by evaporating the solution to dryness in vacuo. This salt is surprisingly nontoxic, and enables the combination of gold therapy with sulfonamide therapy in a single, readily-absorbable drug.

The insoluble, S-(heavy-metal) derivatives of the N (mercapto-acyl) -(p-amino-benzene-sulfonamides) generally may be solubilized by conversion into the sodium salts (or salts with other bases) in the manner detailed in Example 15.

Manifestly, a large number and variety of other N (mercapto acyl) (p amino-benzene-sulfonamides) may be obtained by the procedures of Examples 1, 2 and 3, using the appropriate mercapto-carboxylic acid (I) and p-aminobenzene-sulfonamide (l1) reactants. The following additional reactants (I) and (II), inter alia, may be used for the preparation of the compounds of this invention:

p-Mercapto-propionic acid u-Mercapto-propionic acid (thiolactic acid) a-Mercapto-butyrie acid a-Mercapto-isobutyric acid a-Phenyl-thioglycolic acid Thiomalic acid o-Mercapto-benzoic acid smart? phenyl- Manifestly, also, a large number and variety of other S-(heavy-metal) derivatives of N -(mercapto acyl) (p amino-benzene-sulfonamides, and salts thereof, may be obtained by the procedure of Examples 4 to 12 inclusive, using the appropriate N -(mercapt0-acy1) -(p amino-ben-= zene-sulfonamide) and heavy-metal compound (III) reactants. The following additional reactants (III), inter alia, may be used for the preparation of the S-(heavy-metal) derivatives of this invention:

Arsenous chloride Cupric sulfate Ferric chloride The N (mercapto-acyl) -(p-amino-benzene+ sulfonamides) and salts thereof with bases are. promising chemotherapeutic agents for various infections, and are especially valuable as intermediates for the preparation of the chemotherapeutic S-(heavy-metal) derivatives of the N -(mercapto-acyl)-p-aminobenzene sulfonamides). These heavy-metal derivatives and salts thereof are in general readily-absorbable compounds in which the heavy-metal is bound tightly enough not to cause local toxicity and yet loosely enough to provide a therapeuticallyeffective supply of the metal. Agents for the treatment of infectious arthritis, gonorrhea, syphilis, kala azar, bovine mastitis, tuberculosis, and lymphogranuloma venereum, inter alia, may be obtained by converting the N -(mercaptoacyl)-(p-amino-benzene-sulfonamides) into S- (heavy-metal) derivatives of the appropriate therapeutic heavy-metal.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A compound of the general formula wherein R. represents the N -radical of a pamino-benzene-sulfonamide.

2. N -thioglycolyl-sulfathiazole, represented by the structural formula 3. The method which comprises heating a mixture composed of a p-amino-benzene-sulfonamide and an acid of the general formula n-s-on-ooon wherein R. represents a member of the class consisting of hydrogen, alkyl, aryl, and aralkyl.

I amino-benzene-sulfonamide,

4. The method which comprises heating a compound of the general formula wherein R" representsthe N -radical of a pamino benzene sulfonamide and R" -CO represents an acyl radical, in solution, witha soluble compound of a heavy metal.

, 5, A compound of the class consisting of [A] compounds of the general formula wherein R" represents the N -radical of a pamino-benzene-sulfonamide, and R"'CO- represents an acyl radical; [B] heavy-metal derivatives of [A], wherein the metal is directly linked to the S in the general formula; [C] salts of [A] with bases; and [D] salts of [B] with bases.

6. A compound of the general formula R-[SiHC-R] I whereinrR." represents the N -radical of a p- R represents a member of the class consisting of hydrogen, alkyl, aryl, and aralkyl, R represents a member of the class consisting of hydrogen and the heavy metals, and :1: represents the valence of R.

'7. A heavy-metal derivative of a compound of the general formula H-S -R."'-COR", wherein R" represents the N -radical of a paminobenzene-sulfonamide, R"'-C0 represents an acyl radical, and wherein the metal is directly linked to the S in the general formula.

8; A heavy-metal derivative of a compound of the 'general formula I-I S CH2,CO- f, whereinRf represents the N radical of a pamino-benzene-sulfonamide, and- 'the metal is directly'linked to the S in the general formula. I 9. A bismuth derivative of a compound of the general formula H-S- "'CO- wherein R" represents the N -radica1 of a p-aminobene zenesulfonamide, R." -CO represents an acyl radical, and wherein the bismuth is directly linked to the S in the general formula.

10. A compound of the general formula ui I 'o II I I wherein R" represents the N -radical of a p-' aminobenzene-sulfonamide, and R'CO-- represents an acyl radical. 1 I r WILLIAM A. LOTT.

- KATHRYN A. LOSEE. ANDREW ELLIs OKEEFFE.

REFERENCES crrnn The following references are of record in the file of this patent: UNITED ST T P 'I IS.

Number Name I I I Date 2,270,616 Behnisch' Jan. 20, 1942 2,260,632 Moore Oct. 23, 1941 2,289,029 Mietsch July 7, 1942 2,300,676 Kharasch et al Nov. 3, 1942 2,303,698 Kharasch et al. Dec. 1, 1942 2,295,867 Roblin et al. Sept. 15, 1942 2,324,013 Moore July 13, 1943 

